Project Summary Despite uncertainty surrounding the exact molecular cause of neurodegeneration, a common feature is the accumulation and aggregation of neuronal protein fragments resulting from an increase in their production, or a decrease in their removal. The overall goal of this research is to understand the effects of aggregation-prone protein fragments on normal cell function and to identify cellular pathways involved in the removal of toxic protein species. Previously we found that the N-end rule pathway of the ubiquitin-proteasome system is able to degrade specific protein fragments associated Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis and frontotemporal lobar degeneration. This exciting discovery suggests that defects in the N-end rule pathway may contribute to neurodegeneration. To test this, we will investigate the transgenic expression of a specific disease-associated fragment of the human TDP43 protein in a number of settings including mice, yeast, and in cell culture. These studies will determine if protein fragments of TDP43 play a causative role in disease, and if the loss of their removal by the N-end rule pathway leads to neurodegeneration, in vivo. In addition, these studies generate a number of genetic tools, including a novel mouse model, that will be a valuable resource for the neurodegeneration field, and may ultimately help lead to therapies aimed at preventing neurodegeneration in humans.